Pathogenesis of kidney disease in type 1 diabetes: a modern kidney biopsy cohort

项目总结/摘要 该项目将建立一个新的肾脏活检队列，以表征分子，形态和代谢 1型糖尿病（T1 D）的现代临床病程中糖尿病肾病（DKD）的特征。地标 肾活检研究提高了我们对DKD发病机制的认识。然而， 连续葡萄糖监测和自动胰岛素输注改变了糖尿病管理， T1 D中DKD的临床病程。此外，分子方法的创新，以询问肾脏组织，如 单细胞RNA测序（scRNA-seq）允许以以前没有的分辨率表征DKD 可能根据已发表的工作和我们的初步数据，我们假设，扰动肾脏能量学 缺氧是T1 D DKD发生的主要代谢途径。我们将通过以下方式检验这一假设： 创建一个独特的新的纵向肾脏活检队列（N=100），跨越T1 D的关键持续时间， DKD启动和进展（5-30年），并利用我们现有的先锋活检队列（N=30）。 将从我们现有的健康对照组（N=20）、肾活检组（N=20）和肾活检组（N=20）中提供正常肾活检数据。 精准医学项目（KPMP）和额外的活体肾脏供体活检。我们将实施国家- 最先进的分子（scRNA-seq）和肾组织的形态学检查以及严格的代谢 表型分析具体来说，我们的目标是：（1）确定肾能量学和缺氧过程中的差异， （2）测试缺氧的转录组学特征与结构性病变和临床 进行性DKD的临床表现;（3）探讨肾脏能量学紊乱的机制相关性 和缺氧的T1 D参与者与重复肾活检的一个子集。这项工作将有助于确定 能量紊乱和缺氧在DKD中的作用以及肾脏损害的危险因素和后果 T1 D缺氧。这项研究还将产生一个有价值的数据库，生物样本和肾脏组织， T1 D中DKD的进一步分析，通过KPMP平台公开提供。

Project Summary/Abstract This project will build a new kidney biopsy cohort to characterize the molecular, morphometric, and metabolic features of diabetic kidney disease (DKD) over the modern clinical course of type 1 diabetes (T1D). Landmark kidney biopsy studies have enhanced our understanding of DKD pathogenesis. However, advances in continuous glucose monitoring and automated insulin delivery have changed diabetes management and the clinical course of DKD in T1D. Moreover, innovation in molecular methods to interrogate kidney tissue, such as single-cell RNA sequencing (scRNA-seq), allows characterization of DKD at a resolution not previously possible. Based on published work and our preliminary data, we hypothesize that perturbed kidney energetics and hypoxia are central metabolic pathways in the development of DKD in T1D. We will test this hypothesis by creating a unique new longitudinal kidney biopsy cohort (N=100) spanning the critical duration of T1D over which DKD initiates and progresses (5-30 years) and leveraging our existing vanguard biopsy cohort (N=30). Normative kidney biopsy data will be provided from our existing cohort of healthy controls (N=20), the Kidney Precision Medicine Project (KPMP), and additional living kidney donor biopsies. We will implement state-of- the-art molecular (scRNA-seq) and morphometric interrogation of kidney tissue and rigorous metabolic phenotyping. Specifically, we aim to: (1) define differences in kidney energetics and hypoxia over the course of T1D; (2) test associations of the transcriptomic signatures of hypoxia with the structural lesions and clinical manifestations of progressive DKD; and (3) explore the mechanistic correlates of perturbed kidney energetics and hypoxia within a subset of participants with T1D with repeat kidney biopsies. This work will help define the role of perturbed energetics and hypoxia in DKD as well as risk factors for and consequences of kidney hypoxia in T1D. This study will also generate a valuable repository of data, biosamples, and kidney tissue for further analysis of DKD in T1D, made publicly available through the KPMP platform.